DESCRIPTION: Recent advances in prenatal diagnostics have increased the need for a variety of fetal interventions. Many such procedures can be performed laparoscopically to ameliorate many risks associated with open surgery, but for many patients, the risks of these procedures still outweigh the potential benefits. One major complication associated with fetal surgery is premature rupture of the amniotic sac, or fetal membranes, at the site of membrane puncture during surgery. Such ruptures lead to preterm birth, amniotic fluid leakage, and/or fetal death, and are present in approximately 6-45% of fetoscopy cases. As fetal membrane defects do not heal, there is a growing awareness that novel materials are needed to seal the fetal membranes after surgical intervention. Although several materials have been proposed, none have proven ideal. As a result, the continued inability to seal fetal membranes has been deemed the Achilles heel of fetal surgery. The ideal adhesive for sealing iatrogenic membrane defects needs to have high cohesive strength within the material itself, as well as strong adhesion to wet membrane surfaces. While we as well as other researchers have investigated the concept of applying a sealant or plug material to the membrane defect after the removal of instruments from the fetal sac, a growing body of in vitro evidence suggests that applying a sealant to the surface of the fetal membrane before membrane puncture stabilizes the membrane during surgery by creating a bridge between the fetal membrane and surrounding uterine muscle. Coupled with an effective sealant material, this novel clinical vision of pre-sealing may prevent amniotic fluid leakage out of the amniotic sac and reduce the risks of post-operative membrane rupture. In the proposed work, we will take a bioinspired approach to develop novel polymer hydrogel sealants that will be used in a pre-sealing context. Our strategy will exploit native chemical ligation (NCL) for its chemospecificity and its ability to rapidly cross-link polymer sealants, whereas catechols inspired by wet marine adhesives will provide adhesion of the sealant to the tissue. We will further integrate noncovalent gel strengthening mechanisms into the sealant design, by incorporating energy dissipating metal coordination bonds and hydrophobic domains into the polymer structure. The biological and mechanical properties of the sealants will be examined using in-vitro primary human chorion cell culture, ex vivo human fetal membrane organ culture, and biomechanical sealing studies. Finally, a pregnant rabbit model will be used to demonstrate the efficacy of the sealants described above and the feasibility of pre-sealing of fetal membranes in vivo. By combining innovative design of novel polymer sealants with a unique surgical perspective, this project has the potential to dramatically improve fetal surgery outcomes.